Project Summary/Abstract: Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease in the CNS. It is generally believed that MS and its animal model, experimental autoimmune encephalomyelitis (EAE), are initiated by an autoimmune reaction against oligodendrocytes and myelin. Evidence suggests that oligodendrocyte death induced by inflammatory attacks contributes significantly to the development of MS and EAE. Nuclear Factor ? B (NF-?B) plays a critical role in inflammatory diseases, including MS and EAE, by regulating inflammation and cell viability. Although activation of NF-?B has been observed in oligodendrocytes in MS and EAE, the effects of NF-?B on oligodendrocytes in these diseases remain largely unexplored. In vitro studies from our lab and other groups show that NF-?B activation promotes oligodendrocyte survival in response to inflammatory mediators. Our recent study shows that activation of pancreatic endoplasmic reticulum kinase (PERK) signaling in oligodendrocytes protects mice against EAE and that the protective effects of PERK signaling on oligodendrocytes during EAE are associated with NF-?B activation. Importantly, our preliminary data showed that NF-?B inactivation specifically in oligodendrocytes exacerbated interferon-? (IFN-?)-induced myelinating oligodendrocyte death and hypomyelination in young, developing mice. Our preliminary observation also suggested that NF-?B inactivation specifically in oligodendrocytes significantly increased EAE disease severity. Therefore, we hypothesize that NF-?B activation acts cell-autonomously to protect oligodendrocytes against inflammatory attacks in MS and EAE and accounts for the protective effects of PERK activation on oligodendrocytes in these diseases. In the first specific aim, we will determine whether NF-?B inactivation acts in a cell-autonomous manner to render (re)myelinating oligodendrocytes vulnerable to the detrimental effects of IFN-?, a key proinflammatory cytokine in MS and EAE. In the second specific aim, we will determine whether NF-?B activation cell-autonomously protects oligodendrocytes against inflammatory attacks, resulting in attenuation of EAE disease severity. In the third specific aim, we will determine whether NF-?B activation is required for the protective effects of PERK signaling on oligodendrocytes during EAE. This work will define the cytoprotective effects of the NF-?B pathway, particularly the PERK-NF-?B pathway, on oligodendrocytes (both mature and remyelinating oligodendrocytes) in MS and EAE, which will advance our understanding of the mechanisms governing oligodendrocyte viability in MS.